EnergyReleasing WaterSoluble Vitamins

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considered as properties of the energy­releasing vitamins as a class, rather than being specific for any one.
Figure 28.7 Structure of thiamine.
28.6— Energy­Releasing Water­Soluble Vitamins
Thiamine (Vitamin B1) Forms the Coenzyme Thiamine Pyrophosphate (TPP)
Thiamine (Figure 28.7) is rapidly converted to the coenzyme thiamine pyrophosphate (TPP), which is required for the key reactions catalyzed by pyruvate dehydrogenase complex and a ­ketoglutarate dehydrogenase complex (Figure 28.8). Cellular energy generation is severely compromised in thiamine deficiency. TPP is also required for the transketolase reactions of the pentose phosphate pathway. While the pentose phosphate pathway is not quantitatively important in terms of energy generation, it is the sole source of ribose for the synthesis of nucleic acid precursors and the major source of NADPH for fatty acid biosynthesis and other biosynthetic pathways. Red blood cell transketolase is also the enzyme most commonly used for measuring thiamine status in the body. TPP appears to function in transmission of nerve impulses. TPP (or a related metabolite, thiamine triphosphate) is localized in peripheral nerve membranes. It appears to be required for acetylcholine synthesis and may also be required for ion translocation reactions in stimulated neural tissue.
Although the biochemical reactions involving TPP are fairly well characterized, it is not clear how these biochemical lesions result in the symptoms of thiamine deficiency. The pyruvate dehydrogenase and transketolase reactions are the most sensitive to thiamine levels. Thiamine deficiency appears to selectively inhibit carbohydrate metabolism, causing an accumulation of pyruvate. Cells may be directly affected by lack of available energy and NAPDH or
Figure 28.8 Summary of important reactions involving thiamine pyrophosphate. The reactions involving thiamine pyrophosphate are indicated in red.
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may be poisoned by the accumulated pyruvate. Other symptoms of thiamine deficiency involve the neural tissue and probably result from the direct role of TTP in nerve transmission.
Loss of appetite, constipation, and nausea are among the earliest symptoms of thiamine deficiency. Mental depression, peripheral neuropathy, irritability, and fatigue are other early symptoms and probably directly relate to the role of thiamine in maintaining healthy nervous tissue. These symptoms of thiamine deficiency are most often seen in the elderly and low­income groups on restricted diets. Symptoms of moderately severe thiamine deficiency include mental confusion, ataxia (unsteady gait while walking and general inability to achieve fine control of motor functions), and ophthalmoplegia (loss of eye coordination). This set of symptoms is usually referred to as Wernicke–Korsakoff syndrome and is most commonly seen in chronic alcoholics (see Clin. Corr. 28.5). Severe thiamine deficiency is known as beriberi. Dry beriberi is characterized primarily by advanced neuromuscular symptoms, including atrophy and weakness of the muscles. When these symptoms are coupled with edema, the disease is referred to as wet beriberi. Both forms of beriberi can be associated with an unusual type of heart failure characterized by high cardiac output. Beriberi is found primarily in populations relying exclusively on polished rice for food, although cardiac failure is sometimes seen in alcoholics as well.
The thiamine requirement is proportional to caloric content of the diet and is in the range of 1.0–1.5 mg per day for the normal adult. This requirement should be raised somewhat if carbohydrate intake is excessive or if the metabolic rate is elevated (due to fever, trauma, pregnancy, or lactation). Coffee and tea
CLINICAL CORRELATION 28.5 Nutritional Considerations in the Alcoholic
Chronic alcoholics run considerable risk of nutritional deficiencies. The most common problems are neurologic symptoms associated with thiamine or pyridoxine deficiencies and hematological problems associated with folate or pyridoxine deficiencies. The deficiencies seen with alcoholics are not necessarily due to poor diet alone, although it is often a strong contributing factor. Alcohol causes pathological alterations of the gastrointestinal tract that often directly interfere with absorption of certain nutrients. The liver is the most important site of activation and storage of many vitamins. The severe liver damage associated with chronic alcoholism appears to interfere directly with storage and activation of certain nutrients.
Up to 40% of hospitalized alcoholics are estimated to have megaloblastic erythropoiesis due to folate deficiency. Alcohol appears to interfere directly with folate absorption and alcoholic cirrhosis impairs storage of this nutrient. Another 30% of hospitalized alcoholics have sideroblastic anemia or identifiable sideroblasts in erythroid marrow cells characteristic of pyridoxine deficiency. Some alcoholics also develop a peripheral neuropathy that responds to pyridoxine supplementation. This problem appears to result from impaired activation and increased degradation of pyridoxine. In particular, acetaldehyde (an end product of alcohol metabolism) displaces pyridoxal phosphate from its carrier protein in the plasma. The free pyridoxal phosphate is then rapidly degraded to inactive compounds and excreted.
The most dramatic nutritionally related neurological disorder is Wernicke–Korsakoff syndrome. The symptoms include mental disturbances, ataxia (unsteady gait and lack of fine motor coordination), and uncoordinated eye movements. Congestive heart failure similar to that seen with beriberi is also seen in a small number of these patients. While this syndrome may only account for 1–3% of alcohol­related neurologic disorders, the response to supplemental thiamine is so dramatic that it is usually worth consideration. The thiamine deficiency appears to arise primarily from impaired absorption, although alcoholic cirrhosis may also affect the storage of thiamine in the liver.
While those are the most common nutritional deficiencies associated with alcoholism, deficiencies of almost any of the water­soluble vitamins can occur and cases of alcoholic scurvy and pellagra are occasionally reported. Chronic ethanol consumption causes an interesting redistribution of vitamin A stores in the body. Vitamin A stores in the liver are rapidly depleted while levels of vitamin A in the serum and other tissues may be normal or slightly elevated. Apparently, ethanol causes both increased mobilization of vitamin A from the liver and increased catabolism of liver vitamin A to inactive metabolites by the hepatic P450 system. Alcoholic patients have decreased bone density and an increased incidence of osteoporosis. This probably relates to a defect in the 25­hydroxylation step in the liver as well as an increased rate of metabolism of vitamin D to inactive products by an activated cytochrome P450 system. Dietary calcium intake is also often poor. In fact, alcoholics generally have decreased serum levels of zinc, calcium, and magnesium due to poor dietary intake and increased urinary losses. Iron­deficiency anemia is very rare unless there is gastrointestinal bleeding or chronic infection. In fact, excess iron is a more common problem with alcoholics. Many alcoholic beverages contain relatively high iron levels, and alcohol appears to enhance iron absorption.
Hayumpa, A. M. Mechanisms of vitamin deficiencies in alcoholism. Alcohol. Clin. Exp. Res. 10:573, 1986; and Lieber, C. S. Alcohol, liver and nutrition. J. Am. Coll Nutr. 10:602, 1991.
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contain substances that destroy thiamine, but this is not a problem for individuals consuming normal amounts of these beverages. Routine enrichment of cereals has assured that most Americans have an adequate intake of thiamine on a normal mixed diet.
Riboflavin Is Part of FAD and FMN
Riboflavin is the precursor of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), both of which are involved in a wide variety of redox reactions. The flavin coenzymes are essential for energy production and cellular respiration. The most characteristic symptoms of riboflavin deficiency are angular cheilitis, glossitis, and scaly dermatitis (especially around the nasolabial folds and scrotal areas). The best flavin­requiring enzyme for assaying riboflavin status appears to be erythrocyte glutathione reductase. The recommended riboflavin intake is 1.2–1.7 mg day–1 for the normal adult. Foods rich in riboflavin include milk, meat, eggs, and cereal products. Riboflavin deficiencies are quite rare in this country. When riboflavin deficiency does occur, it is usually seen in chronic alcoholics. Hypothyroidism has recently been shown to slow the conversion of riboflavin to FMN and FAD. It is not known whether this affects riboflavin requirements, however.
Niacin Is Part of NAD and NADP
Niacin is not a vitamin in the strictest sense of the word, since some niacin can be synthesized from tryptophan. However, conversion of tryptophan to niacin is relatively inefficient (60 mg of tryptophan is required for the production of 1 mg of niacin) and occurs only after all of the body requirements for tryptophan (protein synthesis and energy production) have been met. Since synthesis of niacin requires thiamine, pyridoxine, and riboflavin, it is also very inefficient on a marginal diet. Thus most people require dietary sources of both tryptophan and niacin. Niacin (nicotinic acid) and niacinamide (nicotinamide) are both converted to the ubiquitous oxidation–reduction coenzymes NAD+ and NADP+ in the body.
Borderline niacin deficiencies are first seen as a glossitis (redness) of the tongue, somewhat similar to riboflavin deficiency. Pronounced deficiencies lead to pellagra, which is characterized by the three Ds: dermatitis, diarrhea, and dementia. The dermatitis is characteristic in that it is usually seen only in skin areas exposed to sunlight and is symmetric. The neurologic symptoms are associated with actual degeneration of nervous tissue. Because of food fortification, pellagra is a medical curiosity in the developed world. Today it is primarily seen in alcoholics, patients with severe malabsorption problems, and elderly on very restricted diets. Pregnancy, lactation, and chronic illness lead to increased needs for niacin, but a varied diet will usually provide sufficient amounts.
Since tryptophan can be converted to niacin, and niacin can exist in a free or bound form, the calculation of available niacin for any given food is not a simple matter. For this reason, niacin requirements are expressed in terms of niacin equivalents (1 niacin equiv = 1 mg free niacin). The current recommendation of the Food and Nutrition Board for a normal adult is 13–19 niacin equivalents (NE) per day. The richest food sources of niacin are meats, peanuts and other legumes, and enriched cereals.
Pyridoxine (Vitamin B6) Forms the Coenzyme Pyridoxal Phosphate
Figure 28.9 Structures of vitamin B6.
Pyridoxine, pyridoxamine, and pyridoxal are all naturally occurring forms of vitamin B6 (Figure 28.9). All three forms are efficiently converted by the body to pyridoxal phosphate, which is required for the synthesis, catabolism, and interconversion of amino acids. The role of pyridoxal phosphate in amino
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acid metabolism has been discussed previously (see p. 449). While pyridoxal phosphate­dependent reactions are legion, there are a few instances in which the biochemical lesion seems to be directly associated with the symptoms of B6 deficiency (Figure 28.10). Pyridoxal phosphate is essential for energy production from amino acids and can be considered an energy­releasing vitamin. Thus some of the symptoms of severe B6 deficiency are similar to those of the other energy­releasing vitamins. Pyridoxal phosphate is also required for the synthesis of the neurotransmitters serotonin and norepinephrine and for synthesis of the sphingolipids necessary for myelin formation. These effects are thought to explain the irritability, nervousness, and depression seen with mild deficiencies and the peripheral neuropathy and convulsions observed with severe deficiencies. Pyridoxal phosphate is required for the synthesis of ­aminolevulinic acid, a precursor of heme. B6 deficiencies occasionally cause sideroblastic anemia, which is characteristically a microcytic anemia seen in the presence of high serum iron. Pyridoxal phosphate is also an essential component of glycogen phosphorylase; it is covalently linked to a lysine residue and stabilizes the enzyme. This role of B6 may explain the decreased glucose tolerance associated with deficiency, although B6 appears to have some direct effects on the glucocorticoid receptor as well. Vitamin B6 is also required for the conversion of homocysteine to cysteine, and hyperhomocysteinemia appears to be a risk factor for cardiovascular disease. Finally, pyridoxal phosphate is one of the cofactors required for the conversion of tryptophan to NAD. While this may not be directly related to the symptomatology of B6 deficiency, a tryptophan load test is a sensitive indicator of vitamin B6 status (see Clin. Corr. 28.6, p. 1124).
Figure 28.10 Important metabolic roles ofpyridoxal phosphate. Reactions requiring pyridoxal phosphate are indicated with red arrows. ALA, ­aminolevulinic acid; aKG, a­ketoglutarate; GPT, glutamate pyruvate aminotransferase; and GOT, glutamate oxaloacetate aminotransferase.
The requirement for B6 in the diet is roughly proportional to the protein content of the diet. Assuming that the average American consumes close to 100 g of protein per day, the RDA for vitamin B6 has been set at 1.4–2.0 mg day–1 for a normal adult. This requirement is increased during pregnancy and lactation and may increase somewhat with age as well. Vitamin B6 is fairly widespread in foods, but meat, vegetables, whole­grain cereals, and egg yolks are among the richest sources.
Evaluation of B6 nutritional status has become a controversial topic in recent years. Some of this controversy is discussed in Clin. Corr. 28.6. It has usually been assumed that the average American diet is adequate in B6 and it is not routinely added to flour and other fortified foods. However, recent nutritional surveys have cast doubt on this assumption. A significant fraction of the survey population was found to consume less than two­thirds of the RDA for B6.
Pantothenic Acid and Biotin Are Also Energy­Releasing Vitamins
Pantothenic acid is a component of coenzyme A (CoA) and the phosphopantetheine moiety of fatty acid synthase and thus is required for the metabolism of all fat, protein, and carbohydrate via the citric acid cycle. More than 70 enzymes have been described to date that utilize CoA or its derivatives. In view of the importance of these reactions, one would expect pantothenic acid deficiencies to be a serious concern in humans. This does not appear to be the case for two reasons: (1) pantothenic acid is very widespread in natural foods, probably reflecting its widespread metabolic role, and (2) most symptoms of pantothenic acid deficiency are vague and mimic those of other B vitamin deficiencies.
Biotin is the prosthetic group for a number of carboxylation reactions, the most notable being pyruvate carboxylase (needed for synthesis of oxaloacetate for gluconeogenesis and replenishment of the citric acid cycle), acetyl­CoA carboxylase (fatty acid biosynthesis), and propionyl­CoA carboxylase (methione, leucine, and valine metabolism). Biotin is found in peanuts, chocolate, and eggs and is synthesized by intestinal bacteria.